HYDROGENATION PROCESS FOR PREPARING OXYCODONE HYDROCHLORIDE FROM 14-HYDROXYCODEINONE

Description

[0001] The present invention concerns an improved process for preparing oxycodone hydrochloride having an improved impurity profile.

[0002] WO2005/097801 (to Euro-Celtique S.A.) describes processes for the preparation of oxycodone hydrochloride having less than 25 ppm of 14-hydroxycodeinone. The processes involve either:

(a) oxidising thebaine to form 14-hydroxycodeinone at a "suitable pH to minimize or eliminate" the production of 8,14-dihydroxy-7,8-dihydroxycodeinone in the 14-hydroxycodeinone. This process is not exemplified.
or

(b) treating previously prepared and isolated oxycodone alkaloid or hydrochloride salt such that oxycodone hydrochloride having less than 25 ppm of 14-hydroxycodeinone is obtained. An exemplified method involves re-hydrogenating the previously prepared and isolated oxycodone alkaloid or hydrochloride salt.

[0003] WO2005/097801, however, does not describe a method for preparing oxycodone hydrochloride having less than 25 ppm of 14-hydroxycodeinone from conventionally prepared 14-hydroxycodeinone in a single step. Furthermore, WO2005/097801 is silent regarding the amounts of 6α-oxycodol produced according to the claimed processes.

[0004] WO2014/022733 (to Johnson Matthey PLC) describes a process for preparing an oxycodone acid adduct, said process comprising hydrogenating a solution of 14-hydroxycodeinone and an acid to form a solution of the oxycodone acid adduct, wherein the hydrogenation is carried out at one or more temperatures greater than ambient temperature in the presence of a hydrogenation catalyst and hydrogen gas, wherein the solution of 14-hydroxycodeinone and acid is heated to temperature before it is exposed to the hydrogen gas, and wherein the solution of oxycodone acid adduct comprises 6α-oxycodol in an amount ≤ 0.800 area % as determined by HPLC.

[0005] However, WO2014/022733 does not describe a one pot process for preparing oxycodone hydrochloride, wherein the pH is in the range of about ≥ 2.5 to about ≤ 4.5. Nor does WO2014/022733 describe a process wherein oxycodone hydrochloride precipitates out of the reaction mixture when the process is carried out in the range of about of ≥ about 30 °C to about ≤ 60 °C.

Summary of the invention

[0006] We have developed an improved process which overcomes the disadvantages associated with prior art methods. In the one pot process of the present invention, oxycodone hydrochloride with reduced level of 6α-oxycodol precipitates out of the alcoholic solution, therefore lessening and in certain embodiments bypassing the need for further purification. The present process is suitable for the large-scale or industrial manufacture of oxycodone hydrochloride.

[0007] In one aspect, therefore, the invention provides a process for preparing oxycodone hydrochloride, said process comprising hydrogenating a reaction mixture comprising 14-hydroxycodeinone starting material in an alcoholic solvent and hydrochloric acid to form oxycodone hydrochloride product, wherein

(a) the hydrogenation is carried out in the presence of a heterogeneous platinum group metal (PGM) catalyst and hydrogen gas,

(b) the hydrogenation is carried out at one or more temperatures greater than 30 °C and below the boiling point of the reaction mixture in the presence of a hydrogenation catalyst and hydrogen gas, wherein the reaction mixture comprising 14-hydroxycodeinone starting material in an alcoholic solvent and hydrochloric acid is heated to one or more temperatures greater than 30 °C and below the boiling point of the reaction mixture before it is exposed to the hydrogen gas,

(c) the oxycodone hydrochloride product comprises 6α-oxycodol in an amount < 0.300 area % as determined by HPLC, wherein the HPLC method is as described in the Examples, and characterized in that

(d) the pH of the reaction mixture comprising 14-hydroxycodeinone starting material in an alcoholic solvent and hydrochloric acid is in the range of ≥ 2.5 to ≤ 4.5; and

(e) the process is carried out in one pot.

Detailed description

[0008] The present invention avoids the need to isolate and purify oxycodone base, which is the product of the conventional synthesis. Also, in carrying out the invention in the pH range of ≥ 2.5 to ≤ 4.5, oxycodone hydrochloride comprising 6α-oxycodol in an amount < 0.300 area % as determined by HPLC is prepared.

[0009] The process comprises hydrogenating 14-hydroxycodeinone in an alcoholic solvent and hydrochloric acid. The alcoholic solvent may be a straight-chain or branched C_1-5-alkanol and may be selected from the group consisting of methanol, ethanol, propanols (n- or i-), butanols (n-, i- or t-) and pentanols. In one embodiment, the alcoholic solvent may be selected from the group consisting of methanol, ethanol, isopropanol, n-propanol, or mixtures thereof. In one embodiment, the alcoholic solvent is ethanol. In another embodiment, the alcoholic solvent is SDA-3A, which is 96% ethanol denatured with 4% methanol.

[0010] The 14-hydroxycodeinone is substantially dissolved in the alcoholic solvent and hydrochloric acid. The dissolution of 14-hydroxycodeinone may be encouraged through the use of an aid such as stirring and/or sonication. The product, oxycodone hydrochloride, is not soluble, and precipitates out of the solution when the temperature of the post-hydrogenation reaction mixture is ≤ 45 °C. However, when the temperature of the post-hydrogenation reaction mixture is ≥ 45 °C, oxycodone hydrochloride is dissolved. When the process is carried out in the range of ≥ 30 °C to ≤ 45 °C, the post-hydrogenation reaction mixture can be heated to ≥ 45 °C after the hydrogen is removed, in order to substantially dissolve the oxycodone hydrochloride. Further filtration (eg. over Celite^™) to remove the catalyst and optionally purification may be carried out.

[0011] The catalyst, hydrochloric acid and/or 14-hydroxycodeinone may be water-wet when used. In this regard, the quantity of water which may be added to the reaction in this way is not detrimental to the process provided the ratio of alcohol solvent : water is sufficiently large such that the oxycodone hydrochloride substantially precipitates out of the reaction mixture.

[0012] The hydrogenation catalyst may be a heterogeneous platinum group metal (PGM) catalyst. The catalyst should be selected such that the catalyst preferentially reduces the double bond between C-7 and C-8 rather than reducing the C=O bond at C-6 (see Figure 1). In one embodiment, the heterogeneous catalyst is a heterogeneous platinum group metal (PGM) catalyst, for example, a heterogeneous palladium or platinum catalyst. In one embodiment, the heterogeneous platinum group metal (PGM) catalyst is a heterogeneous palladium catalyst. Examples of palladium catalysts include but are not limited to colloidal palladium, palladium sponge, palladium plate or palladium wire. Examples of platinum catalysts include but are not limited to colloidal platinum, platinum sponge, platinum plate or platinum wire.

[0013] The heterogeneous PGM metal catalyst may be a PGM on a solid support. The support may be selected from the group consisting of carbon, alumina, calcium carbonate, barium carbonate, barium sulfate, titania, silica, zirconia, ceria and a combination thereof. When the support is alumina, the alumina may be in the form of alpha-Al₂O₃, beta-Al₂O₃, gamma-Al₂O₃, delta-Al₂O₃, theta-Al₂O₃ or a combination thereof. When the support is carbon, the carbon may be in the form of activated carbon (e.g. neutral, basic or acidic activated carbon), carbon black or graphite (e.g. natural or synthetic graphite). An example of a heterogeneous PGM catalyst is palladium on carbon.

[0014] The catalyst loading may be up to about 20 mole%. In one embodiment, the catalyst loading may be up to 10 mole% and, in another embodiment, may be in the range of about 0.1-10.0 mole %.

[0015] While it is typically sufficient for a single charge of hydrogenation catalyst to be added to the reaction mixture, a second or further charge may be added and the hydrogenation continued if it has been determined (e.g. via in-process analysis) that the reaction has not gone to completion and starting material remains.

[0016] Conventionally, the hydrogenation of 14-hydroxycodeinone is carried out at an ambient temperature. By "ambient temperature", we mean a temperature of 30°C or less. In the present process, however, the hydrogenation is carried out at one or more temperatures greater than 30°C and below the boiling point of the reaction mixture. The boiling point of the reaction mixture may vary depending on the pressure under which the hydrogenation reaction is conducted. In one embodiment, the hydrogenation may be carried out at one or more temperatures in the range of ≥ 30 °C to ≤ 85 °C. In one preferred embodiment, the hydrogenation is carried out at one or more temperatures in the range of ≥ 30 °C to ≤ 50 °C, such as 40 °C.

[0017] There is no particular limitation on the pressure at which the hydrogenation is carried out. In this regard, the hydrogenation may conveniently be carried out with an initial hydrogen pressure in the range between 30-55 psi, e.g. 40 ± 5 psi.

[0018] As mentioned above, the hydrogenation is carried out at one or more temperatures greater than 30°C and below the boiling point of the reaction mixture. The skilled person would understand and take into account the pressure of the reaction and the effect that it may have on the boiling point of the reaction mixture.

[0019] In carrying out the process of the invention at a temperature greater than 30°C and below the boiling point of the reaction mixture, in which 14-hydroxycodeinone in an alcoholic solvent and hydrochloric acid is heated to temperature before it is exposed to the hydrogen gas, it is possible to obtain oxycodone hydrochloride with an improved impurity profile. In one embodiment, it is possible to significantly reduce the levels of 6α-oxycodol, an impurity which must be controlled to particular levels specified in Official Monographs such as the US Pharmacopeia. For example, the USP 33 Reissue for Oxycodone Hydrochloride specifies that the acceptance criterion for 6α-oxycodol cannot be more than 0.25%. However, the oxycodone hydrochloride ultimately prepared in a production campaign may have undergone several (or, indeed, many) processing treatments in orderto reduce the level of 6α-oxycodol, as well as other impurities, to sufficiently acceptable low levels in order to conform to the required standard. The processing treatments therefore can typically result in extended processing times on plant and loss in product yield. In carrying out the process of the present invention, however, the formation of 6α-oxycodol can be minimised in the reaction which produces it as an impurity, thus reducing the requirement for further processing.

[0020] Without wishing to be bound by theory, 6-oxycodol does not appear to be generated from oxycodone (see Figure 1). Instead, it appears to be produced from 14-hydroxycodeinone which is reduced to 14-hydroxycodeine and it is this latter compound which results in the formation of 6-oxycodol. The hydrogenation process of the present invention therefore appears to influence the 14-hydroxycodeinone→14-hydroxycodeine→6-oxycodol pathway such that the quantity of 6α-oxycodol formed is at a reduced level. Accordingly, the hydrogenation process of the present invention may immediately meet the acceptance criterion specified for 6α-oxycodol in a single step thus improving the overall synthetic route of the oxycodone hydrochloride by increasing the yield of the desired product of the hydrogenation reaction (by decreasing the quantity of 14-hydroxycodeinone lost to impurity formation), as well as reducing or eliminating the requirement for later processing treatments.

[0021] The present invention provides a process wherein the oxycodone hydrochloride comprises 6α-oxycodol in an amount < 0.300 area % as determined by HPLC in the post-hydrogenation reaction mixture. In some embodiments, the oxycodone hydrochloride comprises 6α-oxycodol in an amount ≤ 0.100 area % as determined by HPLC.

[0022] The pH of the initial reaction mixture is in the range of ≥ 2.5 to ≤ 4.5. In some embodiments, the pH may be ≥ 2.6. In some embodiments, the pH may be ≥ 2.7. In some embodiments, the pH may be ≥ 2.8. In some embodiments, the pH may be ≥ 2.9. In some embodiments, the pH may be ≤ 4.4. In some embodiments, the pH may be ≤ 4.3. In some embodiments, the pH may be ≤ 4.2. In some embodiments, the pH may be ≤ 4.1. In one embodiment, the pH of the initial reaction mixture may be in the range of ≥ 3.0 to ≤ 4.0, such as 3.5. It has been observed that within this pH range the level of 6α-oxycodol may be less than 0.100 area % as determined by HPLC.

[0023] By a process carried out in one pot, we mean a process where successive processes are carried out in a single reactor, namely (a) the reduction of 14-hydroxycodeinone to oxycodone, (b) the formation of oxycodone hydrochloride, (c) the precipitation of oxycodone hydrochloride out of solution.

[0024] Other impurities which are also specified in the Official Monographs include α,β-unsaturated ketones (ABUKs), such as 14-hydroxycodeinone and codeinone. There has been much recent concern over ABUKs due to their proposed biological activities as genotoxins. As such, there is a continuing need to develop processes which produce low ABUK oxycodone alkaloid and low ABUK oxycodone salts, such as low ABUK oxycodone hydrochloride. Without wishing to be bound by theory, it appears that the 14-hydroxycodeinone which may be present as an impurity in oxycodone hydrochloride originates from two sources - firstly, residual unreacted 14-hydroxycodeinone starting material and secondly, indirectly from 8,14-dihydroxy-7,8-dihydrocodeinone which, it has been argued, converts to 14-hydroxycodeinone under acidic conditions. Thus, even if the reactions conditions are capable of driving a reaction to form oxycodone having <10 ppm of 14-hydroxycodeinone, the ABUK, 14-hydroxycodeinone, may be generated during salt formation via the dehydration of 8,14-dihydroxy-7,8-dihydrocodeinone. In this regard, 8,14-dihydroxy-7,8-dihydrocodeinone may be present in the hydrogenation of 14-hydroxycodeinone to oxycodone as it may be present as an impurity in the 14-hydroxycodeinone starting material. It may, therefore, be carried forward in the transformation of 14-hydroxycodeinone to oxycodone, as well as subsequent salt formation to form an oxycodone hydrochloride. Likewise, the ABUK codeinone may be generated during salt formation via the dehydration of the precursor 8-hydroxy-7,8-dihydrocodeinone.

[0025] In one embodiment, therefore, the oxycodone hydrochloride prepared according to the present invention comprises ≤ 50 ppm of an α,β-unsaturated ketone, such as ≤ 25 ppm of an α,β-unsaturated ketone, for example, ≤ 15 ppm of an α,β-unsaturated ketone. In one preferred embodiment, the oxycodone hydrochloride comprises ≤ 10 ppm of an α,β-unsaturated ketone. In another embodiment, the oxycodone hydrochloride is substantially free of an α,β-unsaturated ketone. The α,β-unsaturated ketone may be selected from the group consisting of 14-hydroxycodeinone, codeinone and a mixture thereof. Without wishing to be bound by theory, it is believed that the temperature at which the present invention is carried out (i.e. greater than 30°C and below the boiling point of the reaction mixture) is capable of simultaneously dehydrating 8,14-dihydroxy-7,8-dihydrocodeinone (to produce 14-hydroxycodeinone), hydrogenating 14-hydroxycodeinone (to form oxycodone), dehydrating 8-hydroxy-7,8-dihydrocodeinone, if present (to form codeinone) and hydrogenating codeinone, if present (to form hydrocodone).

[0026] Before the reaction mixture is heated to temperature, the reaction vessel may be purged with one or more nitrogen/vacuum cycles (e.g. one, two, three or four cycles). During purging the reaction mixture may be agitated to encourage removal of dissolved oxygen. After the final purge cycle the vessel may be left under nitrogen and agitated (by either stirring or shaking) whilst the vessel is heated. Once the reaction mixture reaches the desired temperature, the hydrogenation reaction may begin by exposing the reaction mixture to hydrogen gas.

[0027] Alternatively, the reaction mixture may be heated to the desired temperature and held at that temperature before exposing the reaction mixture to the hydrogen gas. In one embodiment, therefore, the reaction mixture may be held at one or more temperatures greater than 30°C and below the boiling point of the reaction mixture for up to 1 minute or more before the hydrogen gas is added. In another embodiment, the reaction mixture may be held at one or more temperatures greater than 30°C and below the boiling point of the reaction mixture for up to 15 minutes or more before the hydrogen gas is added. In yet another embodiment, the reaction mixture may be held at one or more temperatures greater than 30°C and below the boiling point of the reaction mixture for up to about 6 hours or more before the hydrogen gas is added.

[0028] The hydrogenation reaction is carried out for a period of time until it is determined that the reaction is complete. Completion of the reaction may be determined by in-process analysis or by identifying that there is no longer an uptake of hydrogen gas. The reaction mixture may be held at temperature and pressure for up to 24 hours.

[0029] On completion of the reaction, the reaction vessel may be cooled to ambient temperature and purged to remove excess hydrogen gas (or vice versa). The hydrogenation catalyst may be removed by any appropriate method, such as filtration (eg. over Celite^™), and the filtrate (containing the oxycodone hydrochloride) may be further treated as desired.

[0030] The invention will now be described by way of the following non-limiting Examples and Drawings.

Examples

Analytical method

1.1 Reagents and Materials:

[0031] 

Reagent/Material	Suplier
Acetic Acid (HOAC)	J.T. Baker, HPLC Grade
Acetonitrile (ACN), HPLC Grade		Fisher, Optima, HPLC Grade
Sodium	Hydroxide (NaOH), 1.0 N	VWR Scientific Products
1-Decanesulfanate, Sodium salt		HPLC Grade
PTFE HPLC Mobile Phase Filters		E. M. Science
Hydrochloric Acid (HCl)		Fisher Scientific
Methanol		Fisher, Optima, HPLC Grade
Codeine Phosphate		JM Reference Standard
6α-Oxycodol		JM Reference Standard
Oxycodone Hydrochloride		JM Reference Standard
Oxycodone-N-oxide		JM Reference Standard
Thebaine		JM Reference Standard
14-Hydroxycodeinone RS		JM Reference Standard
Triethylamine (TEA) HPLC Grade		Fisher, HPLC Grade
pH 1.68 Buffer		Alfa Aesar, SpecPure
pH 4.00 Buffer		Alfa Aesar, SpecPure
Column	Phenomenex Luna, C18(2), 3 µm, 100 × 4.6 mm OOD-4251-EO

1.2 Instrumentation:

[0032] 

Instrument	Description
Detector	Waters, 2487 UV/VIS Detector
Chromatograph	Waters, 2690 Separations Module
Data System	Chromatography Data System, current JM version
Balance	Mettler-Toledo, Model AT261, DeltaRange
pH Meter	Beckman, Model 320
Purified Water	Milli-Q, A-10 Gradient System

1.3 Operating Conditions:

[0033] 

Conditions	Description
Injection Volume	10 µL
Temperature	35° C
Detection	UV at 280 nm
Flow Rate	1.5 mL/min
Linear Gradient (Mixing) Conditions	Time (min)	% MP A	% MPB	Curve
	initial	100	0	6
	20	90	10	6
	40	0	100	6
	45	0	100	6
	46	100	0	6
	55	100	0	6

[0034] 1.4 Diluent Preparation: Using concentrated HCI and Purified water, prepare a 0.1 N hydrochloric acid solution.

1.5 Mobile Phase Preparation:

[0035] 

Mobile Phase

• Weigh 2.22 g of Decane Sulfonic Acid, Sodium Salt and transfer into a (MP) A: suitable 1 L flask.
• Transfer 750 mL purified water, 100 mL MeOH and 150 mL ACN into the flask.
• Mix well to completely dissolve the ion-pairing salt.
• Add 20.0 mL of HOAc and 1.0 mL of TEA.
• Mix well and adjust the apparent pH to 3.5 with HOAc (or NaOH, ~ 1 N).
• Filter and degas the solution.

Mobile Phase

• Weigh 2.22 g of Decane Sulfonic Acid, Sodium Salt and transfer into a (MP) B: suitable 1 L flask.
• Transfer 450 mL purified water, 400 mL MeOH, and 150 mL ACN into the flask.
• Mix well to completely dissolve the ion-pairing salt.
• Add 20.0 mL of HOAc and 1.0 mL of TEA.
• Mix well and adjust the apparent pH to 3.5 with HOAc (or NaOH, ~ 1 N).
• Filter and degas the solution.

1.6 Retention Times of Specified Analytes:

[0036] 

Analyte	RT (min)	RRT
Oxycodone-N-oxide	5.0	0.26
6α-Oxycodol	11.4	0.60
Codeine	14.4	0.75
Oxycodone	19.1	1.00
14-Hydroxycodeinone	23.0	1.20
Thebaine	33.5	1.75

1.7 Sample Solution Preparation:

[0037] 

• In duplicate, accurately weigh approximately 100 mg of the drug substance into a suitable 25 mL volumetric flask.
• Pipette 5.0 mL of methanol into the flask.
• Mix and sonicate until the sample is dissolved, limit sonication to 1 minute, allow to come to room temperature, then dilute to volume with diluent, and mix well.

1.8 RTM Preparation:

Stock Impurity RTM Solution

[0038] 

• Accurately weigh approximately 20 mg of each appropriate qualified reference impurity standard into a suitable 100 mL volumetric flask.
• Pipette 10.0 mL of methanol into the flask.
• Mix and sonicate until all solids are dissolved, limit sonication to 1 minute, then dilute to volume with diluent, and mix well.

0.5 % Impurity RTM Solution

[0039] 

• Transfer 5.0 mL of the stock impurity solution into a suitable 50 mL volumetric flask.
• Dilute to volume with diluent. Mix well.

1.9 Resolution Solution Preparation:

[0040] 

• Accurately weigh approximately 100 mg of Oxycodone HCI (test sample may be used) into a suitable 25 mL volumetric flask.
• Dilute to volume with the 0.5 % impurity standard solution.

1.10 System Equilibration:

[0041] 

• After purging mobile phase through both reservoirs, pump Mobile Phase B for at least 20 minutes.
• Switch to Initial assay conditions and pump for at least 20 minutes.

1.11 Procedure:

[0042] 

• Separately inject in duplicate: the diluent as a blank and Resolution Solution.
• Inject the 0.5 % RTM solution.
• Ensure that all system suitability requirements are met.
• Perform duplicate injections of each sample preparation.
• Perform a diluent injection at the end of the run.
• Unspecified impurities detected should be identified by relative retention time (RRT) to Oxycodone.

1.12 Calculations:

[0043] Area % Specified Impurity (corrected for RRf):

where: PA = peak area

Imp = impurity

RRf = Relative Response Factor

RRf Factors (Report 2114):
Impurity	RRF
Codeine	1.163
6α-Oxycodol	1.596
Oxycodone-N-oxide	0.927
Thebaine	6.017
14-Hydroxycodeinone	1.238

1.13 Typical Chromatograms

[0044] 

Figure 2 shows a typical chromatogram using 0.1N HCl/water acid solution as blank.

Figure 3 shows a typical chromatogram of the retention time markers (RTM).

Figure 4 shows a typical chromatogram of a 0.5 % Impurity Standard solution

Example 1: Experiment 1 (Table 1)

[0045] Charge to pressure vessel, jacket at 65 °C 30 g 14-hydroxycodeinone (FHC), 20 g water, 57 g ethanol (SDA-3A), 8.0 g 37 % hydrochloric acid (pH 1.5), 0.3 g 5 % Palladium on carbon catalyst (50 % wet).

[0046] Purge reactor with nitrogen, batch temperature to not less than 60 °C.

[0047] Cycle hydrogen to 20 psi four times to establish hydrogen atmosphere.

[0048] Pressurize vessel with hydrogen to 20 psi (pounds per square inch).

[0049] Agitation to 600 rpm, reset jacket to 80 °C.

[0050] After 24 hours, vent hydrogen, purge with nitrogen. Filter (hot) through Celite^™ to remove catalyst. Rinse vessel and filter cake with ethanol (~50 mL). Cool batch to < 5 °C over two hours. Isolate solid by filtration, wash with chilled ethanol.

[0051] The subsequent experiments are carried out in a similar manner, at the temperature, pressure, pH and using the catalyst indicated in Table 1.

Example 2: Analytical results for Experiments 1-6

[0052] 

Table 1	Time	Temp	HCI eq./pH	H2	Catalyst	Impurities (%)
Experiment	hours	°C		psi	5 %, 1.0 wt %	Oxycodol	unspec	total

Temperature and Pressure variation
1*	23	80	1.0 / pH 1.5	~ 20	Pd/C	0.74	1.72	2.48
2*	23.5	30	1.0 / pH 1.5	40-45	Pd/C	0.56	0.65	1.26
3*	26	20	1.0 / pH 1.0	40-45	Pd/C	0.61	0.65	1.33

Catalyst variation
4*	25	40	1.0 / pH 2.0	40-45	Pd/BaSO4	0.58	0.52	1.10
5	24	40	1.0 / pH 4.1	40-45	Pd/Alumina	0.24	1.14	1.39
6*	24.5	40	1.0 / pH 1.0	40-45	Pd/ BaCO3	0.57	0.56	1.18

*Not according to the invention

[0053] From Table 1 some reaction conditions were identified as preferred: hydrogen pressure of 40-45 psi, 5 % Palladium on carbon catalyst at 1 % loading as wet, and reaction temperature of 40 °C (Experiment 5). The next series of experiments is intended to demonstrate reproducibility as well as define the acceptable pH range (Table 2).

Example 3: Experiment 9 (Table 2)

[0054] Charge to pressure vessel, jacket at 40 °C 25 g FHC, 20 g water, 57 g ethanol (SDA-3A), 37 % hydrochloric acid to pH 3.0, 0.25 g 5 % Palladium on carbon catalyst (50 % wet).

[0055] Purge reactor with nitrogen, batch temperature to ~40 °C.

[0056] Cycle hydrogen to 45 psi three times to establish hydrogen atmosphere.

[0057] Pressurize vessel with hydrogen to 45 psi (pounds per square inch).

[0058] Agitation to 600 rpm.

[0059] After 24 hours, vent hydrogen, purge with nitrogen. Heat batch to ~60 °C to dissolve product and filter (hot) through Celite^™ to remove catalyst. Rinse vessel and cake with ethanol (-50 mL). Cool batch to < 5 °C over two hours. Isolate solid by filtration, wash with chilled ethanol. Dry solid under vacuum at ~55 °C, 16.8 g.

Example 4: Experiment 10 (Table 2)

[0060] Charge to pressure vessel, jacket at 40 °C 25 g FHC, 20 g water, 57 g ethanol (SDA-3A), 37 % hydrochloric acid to pH 4.0, 0.25 g 5 % Palladium on carbon catalyst (50 % wet).

[0061] Purge reactor with nitrogen, batch temperature to ~40 °C.

[0062] Cycle hydrogen to 45 psi three times to establish hydrogen atmosphere.

[0063] Pressurize vessel with hydrogen to 45 psi (pounds per square inch).

[0064] Agitation to 600 rpm.

[0065] After 24 hours, vent hydrogen, purge with nitrogen. Heat batch to ~60 °C to dissolve product and filter (hot) through Celite^™ to remove catalyst. Rinse vessel and cake with ethanol (~50 mL). Cool batch to < 5 °C over two hours. Isolate solid by filtration, wash with chilled ethanol. Dry solid under vacuum at -55 °C, 17.4 g.

Example 5: Analytical results for Experiments 7-11

[0066] 

Table 2	pH	Reaction Conditions(24 h)			Impurities (%)
Experiment		T °C	H2 psi	catalyst	Oxycodol	Unspec.	Total
7*	1.1	40	40-45	5 % Pd/C	0.35 %	0.45 %	0.80%
8*	2.0	40	40-45	5 % Pd/C	1.01 %	0.44 %	1.45 %
9	3.0	40	40-45	5 % Pd/C	0.07 %	0.50 %	0.57 %
10	4.0	40	40-45	5 % Pd/C	0.10 %	0.49 %	0.59 %
11*	5.0	40	40-45	5 % Pd/C	0.30 %	0.42 %	0.72 %

*Not according to the invention

Claims

1. A process for preparing oxycodone hydrochloride, said process comprising hydrogenating a reaction mixture comprising 14-hydroxycodeinone starting material in an alcoholic solvent and hydrochloric acid to form oxycodone hydrochloride product, wherein

(a) the hydrogenation is carried out in the presence of a heterogeneous platinum group metal (PGM) catalyst and hydrogen gas,

(b) the hydrogenation is carried out at one or more temperatures greater than 30 °C and below the boiling point of the reaction mixture in the presence of a hydrogenation catalyst and hydrogen gas, wherein the reaction mixture comprising 14-hydroxycodeinone starting material in an alcoholic solvent and hydrochloric acid is heated to one or more temperatures greater than 30 °C and below the boiling point of the reaction mixture before it is exposed to the hydrogen gas,

(c) the oxycodone hydrochloride product comprises 6α-oxycodol in an amount < 0.300 area % as determined by HPLC, wherein the HPLC method is as described in the Examples, and
characterized in that

(d) the pH of the reaction mixture comprising 14-hydroxycodeinone starting material in an alcoholic solvent and hydrochloric acid is in the range of ≥ 2.5 to ≤ 4.5; and

(e) the process is carried out in one pot.

2. A process according to claim 1, wherein the oxycodone hydrochloride product precipitates out of the solution when the process is carried out in the range of ≥ 30 °C to ≤ 45 °C.

3. A process according to claim 1, wherein the oxycodone hydrochloride product is dissolved when the process is carried out in the range of ≥ 45 °C to ≤ 85 °C.

4. A process according any one of the preceding claims, wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol or mixtures thereof

5. A process according to claim 4, wherein the alcoholic solvent is ethanol.

6. A process according to any one of the preceding claims, wherein the heterogeneous platinum group metal (PGM) catalyst is Pd/C.

7. A process according to any one of the preceding claims, wherein the hydrogen gas pressure is between 207-379 kPa (30-55 psi).

8. A process according to claim 7, wherein the hydrogen gas pressure is 276 ± 34 kPa (40 ± 5 psi).

9. A process according to any one of the preceding claims, wherein the hydrogenation is carried out at one or more temperatures in the range of ≥ 30 °C to ≤ 85 °C.

10. A process according to claim 9, wherein the hydrogenation is carried out at one or more temperatures in the range of ≥ 30 °C to ≤ 50 °C.

11. A process according to claim 10, wherein the hydrogenation is carried out at 40 °C.

12. A process according to any one of the preceding claims, wherein the pH is in the range of ≥ 3.0 to ≤ 4.0.

13. A process according to claim 8, wherein the oxycodone hydrochloride product comprises 6α-oxycodol in an amount ≤ 0.100 area % as determined by HPLC.

14. A process according to any one of the preceding claims, wherein the oxycodone hydrochloride product comprises ≤ 25 ppm of an α,β-unsaturated ketone.

15. A process according to any one of the preceding claims, wherein the oxycodone hydrochloride product comprises ≤ a 10 ppm of an α,β-unsaturated ketone.

Ansprüche

1. Prozess zum Herstellen von Oxycodonhydrochlorid, wobei der Prozess Hydrieren einer Reaktionsmischung umfasst, die 14-Hydroxycodeinon-Ausgangsmaterial in einem alkoholischen Lösemittel und Chlorwasserstoffsäure umfasst, um Oxycodonhydrochloridprodukt zu bilden, wobei

(a) die Hydrierung in Gegenwart eines heterogenen Platingruppenmetall(PGM)-Katalysators und Wasserstoffgas ausgeführt wird,

(b) die Hydrierung bei einer oder mehreren Temperaturen höher als 30 °C und unterhalb des Siedepunkts der Reaktionsmischung in Gegenwart eines Hydrierungskatalysators und Wasserstoffgas ausgeführt wird, wobei die Reaktionsmischung, die 14-Hydroxycodeinon-Ausgangsmaterial in einem alkoholischen Lösemittel und Chlorwasserstoffsäure umfasst, auf eine oder mehrere Temperaturen höher als 30 °C und unterhalb des Siedepunkts der Reaktionsmischung erwärmt wird, bevor sie dem Wasserstoffgas ausgesetzt wird,

(c) das Oxycodonhydrochloridprodukt 6α-Oxycodol in einer Menge < 0,300 Flächen-% umfasst, wie durch HPLC bestimmt, wobei das HPLC-Verfahren wie in den Beispielen beschrieben ist, und
dadurch gekennzeichnet, dass

(d) der pH-Wert der Reaktionsmischung, die 14-Hydroxycodeinon-Ausgangsmaterial in einem alkoholischen Lösemittel und Chlorwasserstoffsäure umfasst, im Bereich von ≥ 2,5 bis ≤ 4,5 liegt; und

(e) der Prozess in einem Topf ausgeführt wird.

2. Prozess nach Anspruch 1, wobei das Oxycodonhydrochloridprodukt aus der Lösung ausfällt, wenn der Prozess im Bereich von ≥ 30 °C bis ≤ 45 °C ausgeführt wird.

3. Prozess nach Anspruch 1, wobei das Oxycodonhydrochloridprodukt aufgelöst wird, wenn der Prozess im Bereich von ≥ 45 °C bis ≤ 85 °C ausgeführt wird.

4. Prozess nach einem der vorstehenden Ansprüche, wobei das alkoholische Lösemittel ausgewählt ist aus der Gruppe, bestehend aus Methanol, Ethanol, n-Propanol, Isopropanol oder Mischungen davon.

5. Prozess nach Anspruch 4, wobei das alkoholische Lösemittel Ethanol ist.

6. Prozess nach einem der vorstehenden Ansprüche, wobei der heterogene Platingruppenmetall(PGM)-Katalysator Pd/C ist.

7. Prozess nach einem der vorstehenden Ansprüche, wobei der Wasserstoffgasdruck zwischen 207-379 kPa (30-55 psi) liegt.

8. Prozess nach Anspruch 7, wobei der Wasserstoffgasdruck 276 ± 34 kPa (40 ± 5 psi) beträgt.

9. Prozess nach einem der vorstehenden Ansprüche, wobei die Hydrierung bei einer oder mehreren Temperaturen im Bereich von ≥ 30 °C bis ≤ 85 °C ausgeführt wird.

10. Prozess nach Anspruch 9, wobei die Hydrierung bei einer oder mehreren Temperaturen im Bereich von ≥ 30 °C bis ≤ 50 °C ausgeführt wird.

11. Prozess nach Anspruch 10, wobei die Hydrierung bei 40 °C ausgeführt wird.

12. Prozess nach einem der vorstehenden Ansprüche, wobei der pH-Wert im Bereich von ≥ 3,0 bis ≤ 4,0 liegt.

13. Prozess nach Anspruch 8, wobei das Oxycodonhydrochloridprodukt 6α-Oxycodol in einer Menge von ≤ 0,100 Flächen-% umfasst, wie durch HPLC bestimmt.

14. Prozess nach einem der vorstehenden Ansprüche, wobei das Oxycodonhydrochloridprodukt ≤ 25 ppm eines α,β-ungesättigten Ketons umfasst.

15. Prozess nach einem der vorstehenden Ansprüche, wobei das Oxycodonhydrochloridprodukt ≤ 10 ppm eines α,β-ungesättigten Ketons umfasst.

Revendications

1. Procédé de préparation de chlorhydrate d'oxycodone, ledit procédé comprenant l'hydrogénation d'un mélange réactionnel comprenant une matière première 14-hydroxycodéinone dans un solvant alcoolique et de l'acide chlorhydrique pour former un produit chlorhydrate d'oxycodone, dans lequel

(a) l'hydrogénation est effectuée en présence d'un catalyseur hétérogène à métal du groupe du platine (PGM) et d'hydrogène gazeux,

(b) l'hydrogénation est effectuée à une ou à plusieurs températures supérieures à 30 °C et inférieures au point d'ébullition du mélange réactionnel en présence d'un catalyseur d'hydrogénation et d'hydrogène gazeux, dans lequel le mélange réactionnel comprenant une matière première 14-hydroxycodéinone dans un solvant alcoolique et de l'acide chlorhydrique est chauffé à une ou à plusieurs températures supérieures à 30 °C et inférieures au point d'ébullition du mélange réactionnel avant d'être exposé à l'hydrogène gazeux,

(c) le produit chlorhydrate d'oxycodone comprend du 6α-oxycodol en une quantité < à 0,300 % en surface telle que déterminée par CLHP, dans lequel le procédé de CLHP est tel que décrit dans les Exemples, et
caractérisé en ce que

(d) le pH du mélange réactionnel comprenant une matière première 14-hydroxycodéinone dans un solvant alcoolique et de l'acide chlorhydrique est dans la plage ≥ 2,5 à ≤ 4,5 ; et

(e) le procédé est mis en œuvre dans un seul pot.

2. Procédé selon la revendication 1, dans lequel le produit chlorhydrate d'oxycodone précipite dans la solution quand le procédé est mis en œuvre dans la plage ≥ 30 °C à ≤ 45 °C.

3. Procédé selon la revendication 1, dans lequel le produit chlorhydrate d'oxycodone est dissous quand le procédé est mis en œuvre dans la plage ≥ 45 °C à ≤ 85 °C.

4. Procédé selon l'une quelconque des revendications précédentes, dans lequel le solvant alcoolique est sélectionné dans le groupe consistant en le méthanol, l'éthanol, le n-propanol, l'isopropanol ou les mélanges de ceux-ci.

5. Procédé selon la revendication 4, dans lequel le solvant alcoolique est l'éthanol.

6. Procédé selon l'une quelconque des revendications précédentes, dans lequel le catalyseur hétérogène à métal du groupe du platine (PGM) est Pd/C.

7. Procédé selon l'une quelconque des revendications précédentes, dans lequel la pression en hydrogène gazeux est entre 207-379 kPa (30-55 psi).

8. Procédé selon la revendication 7, dans lequel la pression en hydrogène gazeux est de 276 ± 34 kPa (40 ± 5 psi).

9. Procédé selon l'une quelconque des revendications précédentes, dans lequel l'hydrogénation est mise en œuvre à une ou plusieurs températures dans la plage ≥ 30 °C à ≤ 85 °C.

10. Procédé selon la revendication 9, dans lequel l'hydrogénation est mise en œuvre à une ou plusieurs températures dans la plage ≥ 30 °C à ≤ 50 °C.

11. Procédé selon la revendication 10, dans lequel l'hydrogénation est mise en œuvre à 40 °C.

12. Procédé selon l'une quelconque des revendications précédentes, dans lequel le pH est dans la plage ≥ 3,0 à ≤ 4,0.

13. Procédé selon la revendication 8, dans lequel le produit chlorhydrate d'oxycodone comprend du 6α-oxycodol en une quantité ≤ 0,100 % en surface telle que déterminée par CLHP.

14. Procédé selon l'une quelconque des revendications précédentes, dans lequel le produit chlorhydrate d'oxycodone comprend ≤ 25 ppm d'une cétone α,β-insaturée.

15. Procédé selon l'une quelconque des revendications précédentes, dans lequel le produit chlorhydrate d'oxycodone comprend ≤ 10 ppm d'une cétone α,β-insaturée.

Drawing